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Assessing variation in the potential susceptibility of fish to pharmaceuticals, considering evolutionary differences in their physiology and ecology

Journal article
Authors A. R. Brown
L. Gunnarsson
Erik Kristiansson
C. R. Tyler
Published in Philosophical Transactions of the Royal Society B-Biological Sciences
Volume 369
Issue 1656
Pages Art. no. 20130576
ISSN 0962-8436
Publication year 2014
Published at Department of Mathematical Sciences, Mathematical Statistics
Institute of Biomedicine, Department of Infectious Medicine
Pages Art. no. 20130576
Language en
Links dx.doi.org/10.1098/rstb.2013.0576
Keywords drug target, orthologue, physiology, population ecology, species, susceptibility
Subject categories Medical Biotechnology

Abstract

Fish represent the planet's most diverse group of vertebrates and they can be exposed to a wide range of pharmaceuticals. For practical reasons, extrapolation of pharmaceutical effects from 'model' species to other fish species is adopted in risk assessment. Here, we critically assess this approach. First, we show that between 65% and 86% of human drug targets are evolutionarily conserved in 12 diverse fish species. Focusing on nuclear steroid hormone receptors, we further show that the sequence of the ligand binding domain that plays a key role in drug potency is highly conserved, but there is variation between species. This variation for the oestrogen receptor, however, does not obviously account for observed differences in receptor activation. Taking the synthetic oestrogen ethinyloestradiol as a test case, and using life-table-response experiments, we demonstrate significant reductions in population growth in fathead minnow and medaka, but not zebrafish, for environmentally relevant exposures. This finding contrasts with zebrafish being ranked as more ecologically susceptible, according to two independent life-history analyses. We conclude that while most drug targets are conserved in fish, evolutionary divergence in drug-target activation, physiology, behaviour and ecological life history make it difficult to predict population-level effects. This justifies the conventional use of at least a 10x assessment factor in pharmaceutical risk assessment, to account for differences in species susceptibility.

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